One victim died on the bus and another at the hospital after the violent scenes unfolded during a 21st birthday party, according to reports.
One of the victims is reportedly a 19-year-old woman from Stockton, California, according to The East Bay Times.
The first shooting took place shortly after midnight on Tuesday on an off-ramp on Interstate 580 and the second shooting took place shortly after.
The California Highway Patrol say that the shooter was inside another vehicle on the freeway and that the incident was not random.
The birthday girl was reportedly shot in the leg but is in a stable condition.
The bus driver managed to drive the Oakland Police Eastmont Substation after the shooting.
No arrests have been made and police have not given any motive for the attack.
Last month a 25-year-old woman was shot while riding on a party bus in East Oakland with 30 other passengers, none of whom were injured.